A mutational analysis of cellular resistance to anticancer drugs has been undertaken. Resistance is being investigated at the cellular, molecular and genetic levels, using Adriamycin resistant Chinese hamster V79 mutants as a model system. V79 cells resistant to low levels of Adriamycin have been treated with high levels of drug, second step mutants recovered, and these mutants then characterized for their Adriamycin resistance, resistance to other drugs and radiation, plating efficiency, growth rates and karyotype. Such mutants show a great deal of phenotypic heterogeneity including some which are markedly more sensitive to killing by X-rays and others which have reduced tumorigenic potential in nude mice. The relationships between these phenotypes and increased resistance to Adriamycin are being evaluated. These mutants will be subjected to cybrid and hybrid analysis to determine the mode of transmission of Adriamycin resistance (cytoplasmic or nuclear). If nuclear-encoded, the recessivity or dominance of the mutants will be investigated as well as whether phenotypic pleiotropy is due to multiple genetic changes. The cell cycle specificity of Adriamycin cytotoxicity will be compared to the specificity of drug uptake and of sensitivity to other anticancer drugs. The effect of the hypoxic cell radiosensitizer misonidazole on the phenotypic response to Adriamycin will be investigated using both drug sensitive and resistant cell lines. The effect of Adriamycin upon the interaction of misonidazole and radiation-induced cell killing will also be investigated. The development of resistance to anticancer drugs which inhibit mitochondrial function and structure is also being investigated. Resistant mutants will be characterized genetically to provide information on the control mechanisms involved in the expression of resistance to chemotherapeutic agents - an important cause of failure in the treatment of cancer.